The goal of this Motor Neuron Disease (MND) Program Project Grant is to better understand MND. We plan to elucidate motor neuron-specific properties as well as factors that specifically cause motor neuron death. In some cases, there bay be a common pathway of damage with respect to the MNDs. There is an overall emphasis on genetically inherited MNDs. Some of the topics that we will focus on (e.g., damage from oxidative stress, and problems in DNA repair) may clarify non-MND neurodegenerative diseases. The individual projects are: Project 1 (Siddique)- Gene mapping studies in MN disorders; Project 2 (Roos/Miller)-Neurodegeneration and neuroprotection in MND; Project 3 (Woloschak)- The pathogenesis of MND in the wasted mouse; Core A-Clinical-scientific core that acts as a source of clinical information and specimens for members of the Program Project and involves experimental treatments, studies of sporadic and familial MND, and post-poliomyelitis syndrome; Core B- Administrative core. Our hope is that knowledge gained from the varied Projects in this grant may increase our understanding of human MND and lead to rational and effective treatments.